Project Summary The candidate requests support for a five year program of training and research to better understand how brain biochemistry and neural activity are altered in bipolar disorder. In the proposed training program, the candidate will build upon his previous experience in basic neuroscience research and clinical psychiatry to perform a multidisciplinary project at McLean Hospital and the Beth-Israel Deaconess Medical Center. His training plan includes: 1) training in the application of Magnetic Resonance Spectroscopy (MRS) to in vivo studies of neurotransmitter activity and brain metabolism 2) training in the use of functional Magnetic Resonance Imaging (fMRI) to examine neural network activity 3) training in the design and execution of patient oriented investigation and 4) training in the responsible conduct of research. A hallmark feature of bipolar disorder is that it is episodic in nature with what appear to be spontaneous transitions to pathological states and subsequent reversion to euthymia or transition to another state. There is little understood about the biology that gives rise to this instability in mood state or the processes that make these states transitory. This study proposes that the pathophysiology of bipolar disorder is characterized by: 1) original abnormal functional coupling between the brain regions involved in affective regulation, and 2) compensatory changes in neurotransmission. These alterations set in motion a series of forces that generate instability in brain function. The candidate's research plan seeks to: 1) explore the relationship between brain network activity and mood state in bipolar disorder and 2) test a model of mood state switching that proposes a balance of excitatory and inhibitory neurotransmission that can compensate for trait related alterations in brain network connectivity. This study proposes to address this hypothesis by observing brain network activity as well as measuring neurotransmitters and markers of neuronal activity in vivo. These experiments will be performed in a single cohort of subjects with bipolar disorder longitudinally through clinical states of mania and euthymia. In doing so, this study seeks to minimize many substantial confounds of studying this disorder including disease heterogeneity, diagnostic instability, and medication effects. The broader aim of this research is to understand the physiology of state switching in bipolar disorder. This disorder is a common and debilitating illness and current treatments are only partially effective. An understanding of the physiologic basis of transitions between states will allow the development of better interventions to prevent pathological switching to mania or depression.